Arsenic is one of the chemicals deemed of greatest concern at Superfund sites on the EPA's Office of Solid Waste and Emergency Response (OSWER) list, and has been identified as a potent skin and bladder cancer carcinogen ir highly exposed human populations. But, it is uncertain whether these effects occur at lower environmental!) relevant levels for the US. We propose to build on our large US population based epidemiologic study which wil encompass over 6,000 cancer cases and controls (over 1,200 bladder cancer cases, 1,200 squamous cell carcinoma cases, 1,200 basal cell carcinomas cases, and 1,200 controls) to investigate the impact on arsenic-related cancel risk of inherent and exogenous factors influencing targeted pathways hypothesized to be central to arsenic carcinogenesis: (1) DNA damage and repair, (2) oxidative signaling and (3) methylation. Our database includes environmental samples (e.g., tap water) and biologic samples (e.g., toenail clippings, serum, white blood cell DlSLV providing a rich resource for application of scientific and technologic advances in trace metal detection am speciation, host susceptibility, biologic response and statistical methods. In the proposed study we will add to this resource the collection of urine samples for isolation of urothelial cells and analysis of urinary arsenic metabolites and will continue to cryopreserve lymphocytes, dietary data and a preserved water sample for speciation analysis from our ongoing studies. We propose to investigate the biologic effects of arsenic dose by applying unbiasec approaches (i.e.', microarray and proteomic methods) to clarify: (1) the variability of repeated measures, (2) th< tissue specificity, and (3) the validity of response in humans. Additionally, we will evaluate the effects o environmentally relevant doses of arsenic on the central carcinogenic pathways, and will test the effect of arsenic remediation on identified response biomarkers by performing assays at repeated time intervals after consumptior of arsenic-freei drinking water. We will integrate our findings by exploring novel statistical approaches foi incorporating multiple measures of exposure along with biologic and clinical response in risk assessment. New Hampshire is ideally suited to study the effects of low-dose arsenic exposure since over 20% of the private wells ir the region contain arsenic at levels that are suspected to affect human health. One area with especially high drinking water arsenic concentrations is located adjacent to a Superfund site. Moreover, pur preliminary date suggest an enhanced risk of arsenic-related cancers in the presence PAHs exposure, such as benzo(a)pyrene another exposure of particular concern for Superfund sites. Thus, our study provides a unique opportunity to obtain results directly applicable to the US population.